Cholesterol Crystallization and Atherosclerotic Plaque Dynamics

Atherosclerosis arises from the gradual accumulation of lipids and inflammatory cells within the arterial wall, forming plaques that can compromise vascular integrity. A pivotal feature of advanced lesions is the nucleation and growth of cholesterol crystals, predominantly as cholesterol monohydrate, which perforate the fibrous cap and exacerbate local inflammation. Crystal formation destabilises plaques by enlarging the necrotic core, promoting macrophage and smooth muscle cell death, and triggering innate immune pathways such as the NLRP3 inflammasome. Concurrently, cholesterol crystals alter the mechanical properties of the intima and disrupt endothelial barrier function, facilitating further lipid influx and immune cell recruitment. The dynamic interplay between crystal growth, cellular uptake mechanisms, cytokine release and extracellular lipid deposition drives plaque progression and underlies the risk of rupture and clinical events. Understanding the physicochemical processes of crystallisation alongside the cellular responses offers routes to novel diagnostics and therapies aimed at stabilising high-risk plaques and attenuating chronic vascular inflammation.

Research from Nature Portfolio

Work has demonstrated that endothelial cells, when overloaded with low-density lipoprotein cholesterol, can generate intracellular crystals that are deposited at the basolateral surface, impairing barrier function and exacerbating lesion formation. Elevating intracellular cAMP levels with pharmacological agents not only restores endothelial integrity but also inhibits crystal formation in vitro and in vivo. Targeted delivery of cAMP-enhancing compounds in hyperlipidaemic mouse models reduced crystal burden and attenuated plaque development, highlighting the endothelium as a viable therapeutic target to modulate early crystallisation events and vascular inflammation.

Cholesterol Crystallization and Atherosclerotic Plaque Dynamics publication trend

The graph below shows the total number of articles in cholesterol crystallization and atherosclerotic plaque dynamics across all publications each year (not limited to Nature Index journals).

Technical terms

Cholesterol crystal: Solid precipitate of cholesterol monohydrate that forms within atherosclerotic lesions and contributes to mechanical stress and inflammation.

Atherosclerotic plaque: Localised build-up of lipids, inflammatory cells and connective tissue within the arterial wall, capable of obstructing blood flow and rupturing.

Foam cell: Lipid-laden macrophage or smooth muscle cell that has internalised modified lipoproteins and contributes to plaque growth.

Micropinocytosis: Cellular process of fluid-phase uptake in which small vesicles internalise extracellular material, including crystals.

NLRP3 inflammasome: Multiprotein complex in innate immune cells that activates caspase-1, leading to maturation and release of pro-inflammatory cytokines.

MALDI-MSI (matrix-assisted laser desorption/ionisation mass spectrometry imaging): Analytical technique that maps the spatial distribution of lipid species in tissue sections.

Neutrophil extracellular trap (NET): Web-like DNA and protein structures expelled by neutrophils to trap pathogens, which can also exacerbate sterile inflammation.

References

1. Vascular smooth muscle cells in response to cholesterol crystals modulates inflammatory cytokines release and promotes neutrophil extracellular trap formation. Molecular Medicine (2024).
2. Spatial lipidomic profiles of atherosclerotic plaques: A mass spectrometry imaging study. Talanta (2024).
3. Spatial lipidomics of coronary atherosclerotic plaque development in a familial hypercholesterolemia swine model. Journal of Lipid Research (2024).
4. Hyperlipidemia-induced cholesterol crystal production by endothelial cells promotes atherogenesis. Nature Communications (2017).
5. Cholesterol Crystals Activate the NLRP3 Inflammasome in Human Macrophages: A Novel Link between Cholesterol Metabolism and Inflammation. PLOS ONE (2010).